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L-Arginine is the physiological substrate for the nitric oxide synthase (NOS) family, which synthesises nitric oxide (NO) in endothelial and neuronal cells. NO synthesis can be inhibited by endogenous asymmetric dimethylarginine (ADMA). NO has explicit roles in cellular signalling and vasodilation. Impaired NO bioavailability represents the central feature of endothelial dysfunction associated with vascular diseases. Interestingly, dietary supplementation with L-arginine has been shown to alleviate endothelial dysfunctions caused by impaired NO synthesis. In this study the transport kinetics of [3H]-arginine and [3H]-ADMA into the central nervous system (CNS) were investigated using physicochemical assessment and the in situ brain/choroid plexus perfusion technique in anesthetized mice. Results indicated that L-arginine and ADMA are tripolar cationic amino acids and have a gross charge at pH 7.4 of 0.981. L-Arginine (0.00149±0.00016) has a lower lipophilicity than ADMA (0.00226±0.00006) as measured using octanol-saline partition coefficients. The in situ perfusion studies revealed that [3H]-arginine and [3H]-ADMA can cross the blood-brain barrier (BBB) and the blood-CSF barrier. [3H]-Arginine (11.6nM) and [3H]-ADMA (62.5nM) having unidirectional transfer constants (Kin) into the frontal cortex of 5.84±0.86 and 2.49±0.35 μl.min-1.g-1, respectively, and into the CSF of 1.08±0.24 and 2.70±0.90 μl.min-1.g-1, respectively. In addition, multiple-time uptake studies revealed the presence of CNS-to-blood efflux of ADMA. Self- and cross-inhibition studies indicated the presence of transporters at the BBB and the blood-CSF barriers for both amino acids, which were shared to some degree. Importantly, these results are the first to demonstrate: (i) saturable transport of [3H]-ADMA at the blood-CSF barrier (choroid plexus) and (ii) a significant CNS to blood efflux of [3H]-ADMA. Our results suggest that the arginine paradox, in other words the clinical observation that NO-deficient patients respond well to oral supplementation with L-arginine even though the plasma concentration is sufficient to saturate endothelial NOS, could be related to altered ADMA transport (efflux). [ABSTRACT FROM AUTHOR]

Growing body of evidence suggests that cardiovascular risk factor, asymmetric dimethylarginine (ADMA), can be implicated in the pathogenesis of neurodegenerative and psychiatric disorders. In part, ADMA can affect brain health negatively modulating critical functions of the blood-brain barrier (BBB). The precise mechanisms and consequences of ADMA action on the cerebral vasculature remains unexplored. Here, we evaluated ADMA-induced maladaptation of BBB functions by analyzing real time electrical cell-substrate impedance, paracellular permeability, immune-endothelial interactions, and inflammatory cytokines production by primary human brain microvascular endothelial cells (hBMVEC) treated with ADMA. We found that ADMA disrupted physical barrier function as evident by significant decrease in electrical resistance and increase in paracellular permeability of hBMVEC monolayers. Next, ADMA triggered immune-endothelial interactions since adhesion of primary human monocytes and their extravasation across the endothelialmonolayer both were significantly elevated upon treatment with ADMA. Increased levels of cell adhesion molecules (VCAM-1 and RANTES), VEGF-A and inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-10, IL-4, IL-2, IL-13, IL-12p70) characterize ADMA-induced hBMVEC dysfunction as inflammatory. Overall, our data suggest that ADMA can impair BBB functions disrupting the endothelial barrier and eliciting neuroinflammatory and neuroimmune responses. [ABSTRACT FROM AUTHOR]

Primary Hyperparathyroidism (PHPT) is characterized by excessive parathormone (PTH) secretion and disrupted calcium homeostasis. Untargeted metabolomics offers a valuable approach to understanding the complex metabolic alterations associated with different diseases, including PHPT. Plasma untargeted metabolomics was applied to investigate the metabolic profiles of PHPT patients compared to a control group. Two complementary liquid-phase separation techniques were employed to comprehensively explore the metabolic landscape in this retrospective, single-center study. The study comprised 28 female patients diagnosed following the current guidelines of PHPT diagnosis and a group of 30 healthy females as a control group. To evaluate their association with PHPT, we identified changes in plasma metabolic profiles in patients with PHPT compared to the control group. The primary outcome measure included detecting plasma metabolites and discriminating PHPT patients from controls. The study unveiled specific metabolic imbalances that may link l-amino acids with peptic ulcer disease, gamma-glutamyls with oxidative stress, and asymmetric dimethylarginine (ADMA) with cardiovascular complications. Several metabolites, such as gamma-glutamyls, caffeine, sex hormones, carnitine, sphingosine-1-phosphate (S-1-P), and steroids, were connected with reduced bone mineral density (BMD). Metabolic profiling identified distinct metabolic patterns between patients with PHPT and healthy controls. These findings provided valuable insights into the pathophysiology of PHPT. [ABSTRACT FROM AUTHOR]

Introduction: Asymmetric dimethylarginine (ADMA), a cardiovascular risk factor, increases in renal failure. The aim of this study was to investigate ADMA levels in normal weight and obese patients on hemodialysis. Methods: In this cross-sectional study, 43 normal weight and 43 obese patients on regular hemodialysis were examined. Malnutrition-inflammation score (MIS), anthropometry, circulating ADMA, lipid profiles including triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipid ratios, glucose homeostasis parameters, blood pressure, and high-sensitivity C-reactive protein (hs-CRP) were assessed. Results: Serum levels of ADMA were significantly lower in the obese compared to the normal weight patients (10268.2 ± 10092.4 vs. 13765.2 ± 9951.3 ng/l, P = 0.03). At the same time MIS score (6.1 ± 2.4 vs. 10.7 ± 3.2, P < 0.001), systolic blood pressure (119 ± 26.8 vs. 134.2 ± 24.7 mmHg, P = 0.018) and mean arterial pressure (91.3 ± 18.6 vs. 100.9 ± 15.9 mmHg, P = 0.028) were significantly lower in the obese than the normal weight group. Fasting blood glucose (P = 0.045), TG/HDL (P = 0.03), TC/HDL (P = 0.019), and LDL/HDL (P = 0.005) ratios, and hs-CRP (P = 0.015) levels were significantly higher in the obese than in the normal weight group. Conclusion: Circulating ADMA was significantly lower in obese than in normal weight patients on hemodialysis, which was concomitant with lower MIS, indicating a better nutritional inflammatory status, and lower blood pressure. [ABSTRACT FROM AUTHOR]

Background: Periodontitis, a chronic inflammatory disease, has been associated with an elevated risk of cardiovascular disease (CVD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has emerged as a potential biomarker linking periodontitis, endothelial dysfunction, and CVD. This systematic review aimed to synthesize the existing evidence on the relationship between ADMA, periodontitis, and CVD, and to evaluate ADMA's potential as a biomarker for periodontal disease progression and its correlation with endothelial dysfunction. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases from their inception to March 2023. Observational and interventional studies assessing ADMA levels in patients with periodontitis and/or CVD were included. The methodological quality of the included studies was evaluated using the NIH Quality Assessment Tools. Due to the heterogeneity of the included studies, a qualitative synthesis was performed. Results: Cross-sectional studies consistently demonstrated significantly elevated ADMA levels in patients with periodontitis and CVD compared to healthy controls. The prospective cohort study indicated that successful periodontal treatment was associated with a significant reduction in ADMA levels and concomitant improvement in endothelial function. The pilot cohort study reported a significant decrease in ADMA levels following periodontal therapy in patients with chronic kidney disease. However, the randomized controlled trials did not demonstrate significant alterations in ADMA levels or endothelial function subsequent to periodontal treatment in patients with periodontitis alone. Conclusions: Periodontal treatment may effectively reduce ADMA levels and improve endothelial function, particularly in patients with comorbidities. These findings suggest that ADMA is a promising biomarker linking periodontitis, endothelial dysfunction, and CVD. However, the limitations of this study include the small number of studies, heterogeneity in the study designs, and a lack of long-term follow-up data. Further high-quality, longitudinal studies are required to confirm its clinical utility and elucidate the underlying mechanisms of these relationships. The integration of periodontal care into CVD prevention and management strategies warrants consideration, as it may contribute to mitigating the cardiovascular risk associated with periodontitis. [ABSTRACT FROM AUTHOR]

Abstract Introduction Asymmetric dimethylarginine (ADMA), a cardiovascular risk factor, increases in renal failure. The aim of this study was to investigate ADMA levels in normal weight and obese patients on hemodialysis. Methods In this cross-sectional study, 43 normal weight and 43 obese patients on regular hemodialysis were examined. Malnutrition-inflammation score (MIS), anthropometry, circulating ADMA, lipid profiles including triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipid ratios, glucose homeostasis parameters, blood pressure, and high-sensitivity C-reactive protein (hs-CRP) were assessed. Results Serum levels of ADMA were significantly lower in the obese compared to the normal weight patients (10268.2 ± 10092.4 vs. 13765.2 ± 9951.3 ng/l, P = 0.03). At the same time MIS score (6.1 ± 2.4 vs. 10.7 ± 3.2, P

Abstract Background Optimal balance between macro- and microcirculation in critically ill patients is crucial for ensuring optimal organ perfusion. Nitric oxide (NO) is a regulator of vascular hemostasis and tone. The availability of NO is controlled by asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the availability of the NO substrates arginine and homoarginine. We investigated the changes in plasma concentrations of ADMA, SDMA, arginine, and homoarginine days 1–5 of intensive care unit (ICU) admission and the association between the change in concentration days 1–3 and 30-day all-cause mortality. Methods Single-center cohort study of adult critically ill patients from the ICU at Copenhagen University Hospital – North Zealand. ADMA, SDMA, arginine, and homoarginine (NO-biomarkers) were measured on days 1–5. Initially, we determined the changes in NO-biomarkers days 1–5 with linear mixed models, and subsequently how the changes in NO-biomarkers days 1–3 were associated with 30-day all-cause mortality. Post-hoc we analyzed the association between plasma concentration at admission and 30-day all-cause mortality. Results In total 567 out of 577 patients had plasma samples from days 1–5. Plasma concentrations of ADMA and arginine increased from days 1–5. SDMA concentrations increased from days 1–2, followed by a decrease from days 2–5. Concentrations of homoarginine did not change from days 1–3 but slightly increased from days 3–5. In total 512 patients were alive 3 days after ICU admission. Among these patients, a daily twofold increase in ADMA concentration from days 1–3 was associated with decreased mortality in multivariate analysis (HR 0.45; 95% CI 0.21–0.98; p = 0.046). An increase in SDMA, arginine, or homoarginine was not associated with mortality. Post-hoc we found that a twofold increase in ADMA or SDMA concentrations at admission was associated with mortality (HR 1.78; 95% CI 1.24–2.57; p = 0.0025, and HR 1.41; 95% CI 1.05–1.90; p = 0.024, respectively). Conclusions Increasing ADMA concentrations on days 1–3 are inversely associated with mortality, however not with the same strength as high ADMA or SDMA concentrations at admission. We suggest that admission concentrations are the focus of future research on ADMA and SDMA as predictors of mortality or potential therapeutical targets in ICU patients.

Background: Optimal balance between macro- and microcirculation in critically ill patients is crucial for ensuring optimal organ perfusion. Nitric oxide (NO) is a regulator of vascular hemostasis and tone. The availability of NO is controlled by asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the availability of the NO substrates arginine and homoarginine. We investigated the changes in plasma concentrations of ADMA, SDMA, arginine, and homoarginine days 1–5 of intensive care unit (ICU) admission and the association between the change in concentration days 1–3 and 30-day all-cause mortality. Methods: Single-center cohort study of adult critically ill patients from the ICU at Copenhagen University Hospital – North Zealand. ADMA, SDMA, arginine, and homoarginine (NO-biomarkers) were measured on days 1–5. Initially, we determined the changes in NO-biomarkers days 1–5 with linear mixed models, and subsequently how the changes in NO-biomarkers days 1–3 were associated with 30-day all-cause mortality. Post-hoc we analyzed the association between plasma concentration at admission and 30-day all-cause mortality. Results: In total 567 out of 577 patients had plasma samples from days 1–5. Plasma concentrations of ADMA and arginine increased from days 1–5. SDMA concentrations increased from days 1–2, followed by a decrease from days 2–5. Concentrations of homoarginine did not change from days 1–3 but slightly increased from days 3–5. In total 512 patients were alive 3 days after ICU admission. Among these patients, a daily twofold increase in ADMA concentration from days 1–3 was associated with decreased mortality in multivariate analysis (HR 0.45; 95% CI 0.21–0.98; p = 0.046). An increase in SDMA, arginine, or homoarginine was not associated with mortality. Post-hoc we found that a twofold increase in ADMA or SDMA concentrations at admission was associated with mortality (HR 1.78; 95% CI 1.24–2.57; p = 0.0025, and HR 1.41; 95% CI 1.05–1.90; p = 0.024, respectively). Conclusions: Increasing ADMA concentrations on days 1–3 are inversely associated with mortality, however not with the same strength as high ADMA or SDMA concentrations at admission. We suggest that admission concentrations are the focus of future research on ADMA and SDMA as predictors of mortality or potential therapeutical targets in ICU patients. [ABSTRACT FROM AUTHOR]

Featured Application: In this study, we evaluated the relationship among the carotid intima–media thickness (CIMT), the redox balance parameters of plasma asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), and HO-1, and the expression of oxidative stress-related NF-kB, Nrf2, and HO-1 in peripheral blood mononuclear cells as biomarkers in metabolic syndrome (MetS). Metabolic syndrome (MetS) is defined by the World Health Organisation (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidaemia. The components of MetS and the associated cardiovascular risks may disrupt the vascular endothelial function and the structure of the vascular wall, increasing the risk of atherosclerosis and vascular diseases. In this study we evaluated the relationship between the carotid intima–media thickness (CIMT), the redox balance parameters of plasma asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), and heme oxygenase 1 (HO-1), and the expression of oxidative stress-related nuclear factor kappa B (NF-kB), nuclear factor erythroid 2-related factor 2 (Nrf2), and HO-1 in peripheral blood mononuclear cells (PBMCs) in MetS. Significantly higher CIMT was established in MetS patients aged ≥ 55 years as compared with the control group (0.96 ± 0.29 vs. 0.74 ± 0.21, p < 0.05). Expression was higher in MetS patients aged < 55 years (83% for NF-kB, p < 0.05; 251% for Nrf2, p < 0.05, and 337% for HO-1, p < 0.05) in comparison to the control group. Similarly, expression was higher in CIMT < 0.90 mm than the control group by 80% for NF-kB, p < 0.01; 260% for Nrf2, p < 0.05, and 303% for HO-1, p < 0.05. In contrast, gene expression was under-regulated in the subgroups of MetS patients aged ≥ 55 years and MetS patients with CIMT ≥ 0.90 mm. Significantly higher plasma levels for MDA, ADMA, and HO-1 were established in the age < 55 and age ≥ 55 MetS subgroups and the CIMT < 0.90 mm and CIMT ≥ 0.90 mm subgroups. In conclusion, MetS individuals aged ≥ 55 are at higher risk of increased CIMT and impaired redox balance. [ABSTRACT FROM AUTHOR]

This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Healthy aging has emerged as a crucial issue with the increase in the geriatric population worldwide. Food-derived sulfur-containing amino acid ergothioneine (ERGO) is a potential dietary supplement, which exhibits various beneficial effects in experimental animals although the preventive effects of ERGO on aging and/or age-related impairments such as frailty and cognitive impairment are unclear. We investigated the effects of daily oral supplementation of ERGO dissolved in drinking water on lifespan, frailty, and cognitive impairment in male mice from 7 weeks of age to the end of their lives. Ingestion of 4 ~ 5 mg/kg/day of ERGO remarkably extended the lifespan of male mice. The longevity effect of ERGO was further supported by increase in life and non-frailty spans of Caenorhabditis elegans in the presence of ERGO. Compared with the control group, the ERGO group showed significantly lower age-related declines in weight, fat mass, and average and maximum movement velocities at 88 weeks of age. This was compatible with dramatical suppression by ERGO of the age-related increments in plasma biomarkers (BMs) such as the chemokine ligand 9, creatinine, symmetric dimethylarginine, urea, asymmetric dimethylarginine, quinolinic acid, and kynurenine. The oral intake of ERGO also rescued age-related impairments in learning and memory ability, which might be associated with suppression of the age-related decline in hippocampal neurogenesis and TDP43 protein aggregation and promotion of microglial shift to the M2 phenotype by ERGO ingestion. Ingestion of ERGO may promote longevity and healthy aging in male mice, possibly through multiple biological mechanisms. [ABSTRACT FROM AUTHOR]

The impact of interplanetary (IP) shocks on the Earth's magnetosphere can greatly disturb the geomagnetic field and electric currents in the magnetosphere-ionosphere system. At high latitudes, the current systems most affected by the shocks are the auroral electrojet currents. These currents then generate ground geomagnetically induced currents that couple with and are highly detrimental to ground artificial conductors including power transmission lines, oil/gas pipelines, railways, and submarine cables. Recent research has shown that the shock impact angle, the angle the shock normal vector performs with the Sun-Earth line, plays a major role in controlling the subsequent geomagnetic activity. More specifically, due to more symmetric magnetospheric compressions, nearly frontal shocks are usually more geoeffective than highly inclined shocks. In this study, we utilize a subset (332 events) of a shock list with more than 600 events to investigate, for the first time, shock impact angle effects on the subsequent GICs right after shock impact (compression effects) and several minutes after shock impact (substorm-like effects). We use GIC recordings from the Finnish natural gas pipeline performed near the Mäntsälä compression station in southern Finland. We find that GIC peaks ( > 5 A) occurring after shock impacts are mostly caused by nearly frontal shocks and occur in the post-noon/dusk magnetic local time sector. These GIC peaks are presumably triggered by partial ring current intensifications in the dusk sector. On the other hand, more intense GIC peaks ( > 20 A) generally occur several minutes after shock impacts and are located around the magnetic midnight terminator. These GIC peaks are most likely caused by intense energetic particle injections from the magnetotail which frequently occur during substorms. The results of this work are relevant to studies aiming at predicting GICs following solar wind driving under different levels of asymmetric solar wind forcing. [ABSTRACT FROM AUTHOR]

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been proposed as mediators of endothelial dysfunction. In this study, we aimed to investigate the diagnostic and prognostic role of ADMA and SDMA in acute cerebrovascular disease. A prospective case-control study was performed, enrolling 48 patients affected by ischemic stroke with no cardioembolic origin, 20 patients affected by TIA, 40 subjects at high cardiovascular risk and 68 healthy subjects. ADMA levels were significantly lower in high-risk subjects (18.85 [11.78–22.83] μmol/L) than in patients with brain ischemic event, both transient (25.70 [13.15–40.20] μmol/L; p = 0.032) and permanent (24.50 [18.0–41.33] μmol/L; p = 0.001). SDMA levels were different not only between high-risk subjects and ischemic patients, but also between TIA and stroke patients, reaching higher levels in TIA group and lower levels in stroke group (1.15 [0.90–2.0] vs 0.68 [0.30–1.07] μmol/L; p < 0.001). SDMA was also correlated with short-term prognosis, with lower levels in case of adverse clinical course, evaluated by type of discharge (p = 0.009) and need of prolonged rehabilitation (p = 0.042). The present study highlights the relationship between l -arginine, ADMA, SDMA and acute cerebrovascular events. Therefore, our results suggested a potential role of SDMA as a specific marker of transient ischemic damage and as a short-term positive prognostic marker. • ADMA, SDMA and their ratio with l -arginine are markers of endothelial dysfunction. • SDMA seems to be specific for the diagnosis of transient ischemic damage. • SDMA are inversely proportional to oxidative stress degree and may be a laboratory indicator of the extent of the neurological deficit and as a short-term positive prognostic marker in the patients affected from ischemic stroke. • ADMA, SDMA and their ratio with l -arginine may represent a new diagnostic and prognostic tool in the management of cardio-cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Aims/Background Rosuvastatin is a common lipid-lowering statin on the market, but its impact on the incidence of long-term cardiovascular events is not well clarified. This study aimed to explore the effects of rosuvastatin on serum asymmetric dimethylarginine (ADMA) levels and the incidence of long-term cardiovascular events in patients with hyperlipidaemia and H-type hypertension. Methods This retrospective study included 158 patients with hyperlipidaemia and H-type hypertension who were treated in the Hebei Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine from August 2015 to August 2016. The patients were divided into an occurrence group and a non-occurrence group according to the occurrence of long-term cardiovascular events following the resuvostatin treatment. The changes in blood lipids, blood pressure, serum ADMA levels and vascular endothelial function indexes before and after treatment were compared, and the effect of ADMA on the occurrence of long-term cardiovascular events and its predictive efficacy were analysed using the Spearman correlation test and receiver operating characteristics (ROC) curve. Results After treatment, the levels of serum total cholesterol, low-density lipoprotein cholesterol, triglyceride, serum ADMA and blood pressure became significantly lower (p < 0.001), with high-density lipoprotein cholesterol exhibiting no significant difference. Twenty-two cases developed long-term cardiovascular events after the treatment, with an incidence of 13.92%. The occurrence group had significantly higher serum ADMA levels than the non-occurrence group (p < 0.001). The rosuvastatin treatment also lowered the levels of endothelin-1 and high-sensitivity C-reactive protein and increased the nitric oxide level (p < 0.001). Spearman correlation analysis showed that serum ADMA levels were positively correlated with the occurrence of long-term cardiovascular events (r=0.462, p < 0.001). Meanwhile, according to the ROC curve, serum ADMA had a good predictive efficacy for long-term cardiovascular events, with an area under the curve of 0.885 (95% confidence interval 0.808–0.963; p < 0.001). Conclusion Rosuvastatin can reduce ADMA levels and exert vascular protective effects. The increase in serum ADMA levels is closely related to the occurrence of long-term cardiovascular events in patients with hyperlipidaemia and H-type hypertension, serving as a potential clinical predictor to guide disease prevention and treatment. [ABSTRACT FROM AUTHOR]

Researchers have studied the effects of exercise on serum methyl-arginine and vitamin D metabolites; however, the effects of exercise combined with antioxidants are not well documented. Since oxidative stress affects the metabolism of vitamin D and methyl-arginine, we hypothesised that the antioxidant coenzyme Q10 (CoQ10) might modulate exercise-induced changes. A group of twenty-eight healthy men participated in this study and were divided into two groups: an experimental group and a control group. The exercise test was performed until exhaustion, with gradually increasing intensity, before and after the 21-day CoQ10 supplementation. Blood samples were collected before, immediately after, and 3 and 24 h after exercise. CoQ10, vitamin D metabolites, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, methylarginine, dimethylamine, arginine, citrulline, and ornithine were analysed in serum samples. CoQ10 supplementation caused a 2.76-fold increase in the concentration of serum CoQ10. Conversely, the 25(OH)D3 concentration increased after exercise only in the placebo group. ADMA increased after exercise before supplementation, but a decrease was observed in the CoQ10 supplementation group 24 h after exercise. In conclusion, our data indicate that CoQ10 supplementation modifies the effects of exercise on vitamin D and methyl-arginine metabolism, suggesting its beneficial effects. These findings contribute to the understanding of how antioxidants like CoQ10 can modulate biochemical responses to exercise, potentially offering new insights for enhancing athletic performance and recovery. [ABSTRACT FROM AUTHOR]

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment. [ABSTRACT FROM AUTHOR]

Introduction: Proliferative diabetic retinopathy (PDR) is a common diabetes complication, significantly impacting vision and quality of life. Previous studies have suggested a potential link between arginine pathway metabolites and diabetic retinopathy (DR). Connective tissue growth factor (CTGF) plays a role in the occurrence and development of fibrovascular proliferation (FVP) in PDR patients. However, the relationship between arginine pathway metabolites and FVP in PDR remains undefined. This study aimed to explore the correlation between four arginine pathway metabolites (arginine, asymmetric dimethylarginine[ADMA], ornithine, and citrulline) and the severity of FVP in PDR patients. Methods: In this study, plasma and aqueous humor samples were respectively collected from 30 patients with age-related cataracts without diabetes mellitus (DM) and from 85 PDR patients. The PDR patients were categorized as mild-tomoderate or severe based on the severity of fundal FVP. The study used KruskalWallis test to compare arginine, ADMA, ornithine, and citrulline levels across three groups. Binary logistic regression identified risk factors for severe PDR. Spearman correlation analysis assessed associations between plasma and aqueous humor metabolite levels, and between ADMA and CTGF levels in aqueous humor among PDR patients. Results: ADMA levels in the aqueous humor were significantly greater in patients with severe PDR than in those with mild-to-moderate PDR(P=0.0004). However, the plasma and aqueous humor levels of arginine, ornithine, and citrulline did not significantly differ between mild-to-moderate PDR patients and severe PDR patients (P>0.05). Binary logistic regression analysis indicated that the plasma (P=0.01) and aqueous humor (P=0.006) ADMA levels in PDR patients were risk factors for severe PDR. Furthermore, significant correlations were found between plasma and aqueous humor ADMA levels (r=0.263, P=0.015) and between aqueous humor ADMA and CTGF levels (r=0.837, P<0.001). Conclusion: Elevated ADMA levels in plasma and aqueous humor positively correlate with the severity of FVP in PDR, indicating ADMA as a risk factor for severe PDR. [ABSTRACT FROM AUTHOR]

The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 plays the key role in the metabolism of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis and inducer of superoxide production. The role of the second DDAH isoform DDAH2 in the metabolism of ADMA has been debated; however, recent studies have conclusively demonstrated that this isoform cannot hydrolyze ADMA. The DDAH2 protein regulates several processes associated with cardiometabolic homeostasis, immune function, and other tasks independent of ADMA. DDAH2 has been demonstrated to improve cardiac function, stabilize atherosclerotic plaques, facilitate the regeneration of damaged endothelium in animal models, regulate insulin production, and protect from sepsis. It is crucial to understand the molecular mechanism of DDAH2 to unravel its biological functions and identify novel therapeutic opportunities. The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 metabolizes asymmetric dimethylarginine (ADMA), a critical endogenous cardiovascular risk factor. In the past two decades, there has been significant controversy about whether DDAH2, the other DDAH isoform, is also able to directly metabolize ADMA. There has been evidence that DDAH2 regulates several critical processes involved in cardiovascular and immune homeostasis. However, the molecular mechanisms underpinning these effects are unclear. In this opinion, we discuss the previous and current knowledge of ADMA metabolism by DDAH in light of a recent consortium study, which convincingly demonstrated that DDAH2 is not capable of metabolizing ADMA, unlike DDAH1. Thus, further research in this field is needed to uncover the molecular mechanisms of DDAH2 and its role in various disorders. [ABSTRACT FROM AUTHOR]

Problem: Preterm birth (PTB) is a leading cause of infant mortality and morbidity. The pathogenesis of PTB is complex and involves many factors, including socioeconomy, inflammation and infection. Asymmetric dimethylarginine, ADMA and symmetric dimethylarginine, SDMA are involved in labor as inhibitors of nitric oxide, a known relaxant of the uterine smooth muscles. Arginines are scarcely studied in relation to PTB and we aimed to investigate arginines (ADMA, SDMA and L‐arginine) in women with spontaneous PTB and term birth. Methods of the Study: The study was based on data from the population‐based, prospective cohort BASIC study conducted in Uppsala County, Sweden, between September 2009 and November 2018. Arginines were analyzed by Ultra‐High Performance Liquid Chromatography using plasma samples taken at the onset of labor from women with spontaneous PTB (n = 34) and term birth (n = 45). We also analyzed the inflammation markers CRP, TNF‐R1 and TNF‐R2 and GDF‐15. Results: Women with spontaneous PTB had higher plasma levels of ADMA (p < 0.001), and L‐Arginine (p = 0.03). In addition, inflammation marker, TNF‐R1 (p = 0.01) was higher in spontaneous PTB compared to term birth. Further, in spontaneous PTB, no significant correlations could be observed when comparing levels of arginines with inflammation markers, except ADMA versus CRP. Conclusions: These findings provide novel evidence for the potential involvement of arginines in the pathogenesis of spontaneous PTB and it seems that arginine levels at labor vary independently of several inflammatory markers. Further research is warranted to investigate the potential of arginines as therapeutic targets in the prevention and management of spontaneous PTB. [ABSTRACT FROM AUTHOR]

Objective: The mechanism of asymmetric dimethylarginine (ADMA) in thrombosis in patients with nonvalvular atrial fibrillation (NVAF) is still unclear. Our aim was to investigate the relationship between ADMA and indicators of prethrombotic state in NVAF patients and to analyze the predictive role of ADMA in NVAF thrombosis. Methods: A total of 192 NVAF patients were continuously selected from January 2023 to October 2023. Plasma ADMA levels were measured by high‐performance liquid chromatography. P‐selectin (P‐sel), von Willebrand factor (vWF), D‐dimer (D‐D), and plasminogen activator inhibitor‐1 (PAI‐1) levels were measured by enzyme‐linked immunosorbent assay (ELISA). Nitric oxide (NO) levels were measured by the nitrate reductase assay for plasma nitrite/nitrate, then the Griess method (Shanghai Hailian Biotechnology Co., Shanghai, China) was used to calculate plasma NO levels. Results: In our study, ADMA levels were significantly elevated and positively correlated with P‐sel, vWF, D‐D, and PAI‐1, whereas NO levels were significantly negatively correlated with these prethrombotic factors in NVAF. Furthermore, multifactorial logistic regression analysis showed that ADMA and LA diameter were independent predictors of high thrombosis risk (CHA2DS2‐VASc ≥2 score) in patients with NVAF. Conclusions: Our findings suggested that ADMA correlated with the prethrombotic state in NVAF and that reduction of ADMA levels in NVAF patients may be a novel therapeutic strategy for thrombosis risk reduction. [ABSTRACT FROM AUTHOR]

Objective: The triglyceride-glucose (TyG) index, a reliable substitute indicator of insulin resistance (IR), is considered an independent risk factor for long-term outcomes in patients with cardiovascular disease. However, studies investigating the association between TyG and atherosclerotic cardiovascular disease (ASCVD) are limited and lack direct evidence. We aim to examine the relationship between the TyG index and ASCVD through a comprehensive cross-sectional study. Methods: Overall, 7212 participants from the 1999-2004 National Health and Nutrition Examination Survey were included. The baseline TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. Restricted cubic spline (RCS) regression, univariate logistic regression, and multivariate logistic regression analysis were used to evaluate the association between the TyG index and ASCVD. Results: In the overall population, a multivariate logistic regression analysis showed that the TyG level was not only positively associated with ASCVD [OR (95%CI): 1.29 (1.01,1.64), P=0.042], coronary artery disease (CAD) [OR (95%CI): 1.82(1.33,2.48), P<0.001], and stroke [OR (95%CI): 2.68(1.54,4.69), P=0.002], but also linearly correlated with all three (P-overall<0.001; P-non-linear >0.05). Although the TyG index was not associated with peripheral arterial disease (PAD) [OR (95%CI): 1.00 (0.73,1.36), P>0.900], it showed a U-shaped correlation with PAD (P-overall <0.001; P-non-linear= 0.0085), and the risk of PAD was minimized when TyG=8.67. By incorporating the TyG index into the baseline risk model, the accuracy of ASCVD prediction was improved [AUC: baseline risk model, 0.7183 vs. baseline risk model + TyG index, 0.7203, P for comparison=0.034]. The results of the subgroup analysis were consistent with those of the main analysis. Conclusion: The TyG index was independently associated with ASCVD, CAD, and stroke, suggesting that it may serve as a valid indicator for predicting ASCVD in the entire population. [ABSTRACT FROM AUTHOR]

Growing body of evidence suggests that cardiovascular risk factor, asymmetric dimethylarginine (ADMA), can be implicated in the pathogenesis of neurodegenerative and psychiatric disorders. In part, ADMA can affect brain health negatively modulating critical functions of the blood-brain barrier (BBB). The precise mechanisms and consequences of ADMA action on the cerebral vasculature remains unexplored. Here, we evaluated ADMA-induced maladaptation of BBB functions by analyzing real time electrical cell-substrate impedance, paracellular permeability, immune-endothelial interactions, and inflammatory cytokines production by primary human brain microvascular endothelial cells (hBMVEC) treated with ADMA. We found that ADMA disrupted physical barrier function as evident by significant decrease in electrical resistance and increase in paracellular permeability of hBMVEC monolayers. Next, ADMA triggered immune-endothelial interactions since adhesion of primary human monocytes and their extravasation across the endothelial monolayer both were significantly elevated upon treatment with ADMA. Increased levels of cell adhesion molecules (VCAM-1 and RANTES), VEGF-A and inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-10, IL-4, IL-2, IL-13, IL-12p70) characterize ADMA-induced hBMVEC dysfunction as inflammatory. Overall, our data suggest that ADMA can impair BBB functions disrupting the endothelial barrier and eliciting neuroinflammatory and neuroimmune responses.

Background Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long‐term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross‐sectional studies. We analyzed ADMA, SDMA, and other L‐arginine metabolites to assess their association with AF in the Find‐AF trial. Methods and Results We included 280 patients presenting with acute cerebral ischemia. Patients presenting in sinus rhythm received 7‐day Holter‐ECG. Biomarkers were quantified by ultra‐performance liquid chromatography–tandem mass spectrometry. We also analyzed protein methylation and L‐arginine‐related metabolites in human induced pluripotent stem cell‐derived cardiomyocytes in vitro. ADMA and SDMA were elevated in 44 patients who presented with AF. SDMA, but not ADMA, was significantly elevated in patients newly diagnosed with AF in Holter‐ECG as compared with those in sinus rhythm. SDMA plasma concentration >0.571 μmol/L significantly predicted presence of AF in Holter‐ECG (area under the curve=0.676 [0.530–0.822]; P=0.029; sensitivity 0.786, specificity 0.572). SDMA levels further increased in patients with AF during the first 24 hours in hospital, and ADMA levels remained stable. In vitro, induced pluripotent stem cell‐derived cardiomyocytes showed increased symmetric protein methylation and elevated SDMA during rapid pacing (2.0 Hz versus 0.5 Hz), whereas asymmetric protein methylation and ADMA were unchanged. Conclusions SDMA at admission was significantly elevated in stroke patients presenting with AF and showed a moderate but significant prospective association with previously unrecognized AF. Thus, stroke patients with elevated SDMA concentration at admission may specifically benefit from extended Holter‐ECG monitoring.

Objective: to evaluate laboratory parameters of hemostasis, lipid metabolism and endothelial dysfunction and their relationship in men aged 18–50 years with atherothrombotic (ATS), lacunar (LS) and cardioembolic (CES) stroke. Material and methods. The study included 89 men with ATS (n=36), LS (n=34) and CES (n=19). Neuroimaging, ultrasound and laboratory blood serum analyses were performed in all patients. Results. The mean age of the patients was 42.6±5.3 years. The main risk factors for ATS, LS and CES included: arterial hypertension (75; 97.8 and 73.7% of cases, respectively), dyslipidemia (60; 41.3 and 42.1%), tobacco smoking (71.7; 67.4 and 52.6%), regular alcohol consumption (35; 19.6 and 36.8%), obesity (23.3; 8.7 and 15.8 %), diabetes mellitus (8.3; 6.5 and 10.5 %). Lower tissue plasminogen activator levels were found in patients with CES (2.66±1.77 ng/ml) compared to patients with LS (3.38±3.0 ng/ml) and ATS (3.48±2.45 ng/ml). Plasminogen activator inhibitor-1 levels were significantly increased in all stroke subtypes. The mean level of soluble thrombomodulin was highest in patients with LS (100.86±58.22 pg/ml) compared to patients with ATS (96.37±85.71 pg/ml) and CES (75.28±39.36 pg/ml). The level of asymmetric dimethylarginine was higher in patients with ATS (1.46±0.42 μmol/l) and in patients with LS (0.79±0.37 μmol/l), and in patients with CES (0.4±0.13 μmol/l) it was within the reference values. Conclusion. We noted differences in laboratory parameters of the hemostasis, lipid metabolism and endothelial dysfunction in men aged 18–50 years with different stroke subtypes (ATS, LS and CES), as well as clinical and laboratory correlations.

Introduction. Despite the major successes achieved in the treatment of acute coronary syndromes (ACS), acute myocardial infarction (AMI) remains the main cause of death among the working-age population of Ukraine. The means of treatment of interventional cardiology can actually reduce the mortality of patients with ACS, improve the course of the acute period of the disease and ensure less reduction in the functional capabilities of the heart in the future. Among the many pathogenetic mechanisms of vascular inflammation in coronary heart disease and type 2 diabetes, endothelial dysfunction is the determining factor. The aim of the study. To evaluate the levels of plasminogen activator inhibitor type 1, asymmetric dimethylarginine and endothelial nitric oxide synthase on the 10-14th day in patients depending on the presence or absence of concomitant diabetes type 2 and the type of reperfusion therapy. Materials and methods. 130 patients with acute myocardial infarction were examined, who were divided into 2 groups: 1 group consisted of patients with acute myocardial infarction with accompanying type 2 diabetes (n=73), 2 group – patients with acute myocardial infarction without type 2 diabetes (n =57). The quantitative content of the plasminogen activator inhibitor type 1 (PAI-1) was determined by the immunoenzymatic method using a commercial test system manufactured by Technoclone PAI-1 ELISA Kit (Austria), endothelial nitric oxide synthase (NOS) – Enzyme-Linked Immunosorbent Assay (ELISA) Kit For Nitric Oxide Synthase Endothelial, asymmetric dimethylarginine (ADMA) – Immunodiagnostik ADMA ELISA Kit (Austria). Results. Percutaneous coronary intervention (PCI) contributes to a more significant decrease in the content of the marker of endothelial dysfunction – ADMA and an increase in NOS on the 10-14th day of acute myocardial infarction in comparison with standard therapy. During PCI, the level of PAI-1 did not reliably change during treatment due to post-inflammatory and post-traumatic activation of platelets in the vascular wall. Conclusions. In patients with acute myocardial infarction with type 2 diabetes mellitus, percutaneous coronary intervention contributes to a significant decrease in the content of asymmetric dimethylarginine and an increase in NOS on the 10-14th day of acute myocardial infarction, but was not accompanied by a significant decrease in the level of PAI-1, which in general indicates positive effect of performed myocardial revascularization.

Abstract Background Serum symmetric dimethylarginine (SDMA) is used to screen for renal dysfunction in dogs. The gold standard technique for measuring SDMA, liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) is not widely available. Age‐specific reference intervals for SDMA in older dogs are lacking. Objectives Prospective study in older dogs to validate a commercially available LC‐MS/MS method for SDMA, compare SDMA concentrations with concentrations measured using ELISA and obtain a reference interval (RI) for older dogs using both methods. Animals Client‐owned older dogs undergoing health screening. Methods The LC‐MS/MS method was analytically validated (limit of detection, precision, and linearity). Serum was sent cooled overnight for ELISA or was frozen at −80°C until batch analysis using LC‐MS/MS. Results of LC‐MS/MS and ELISA were compared and RIs for older dogs were calculated according to international guidelines. Results The LC‐MS/MS method showed good linearity (r2 = .99) and precision (coefficient of variation

Introduction: The global healthcare burden of COVID-19 pandemic has been unprecedented with a high mortality. Metabolomics, a powerful technique, has been increasingly utilized to study the host response to infections and to understand the progression of multi-system disorders such as COVID-19. Analysis of the host metabolites in response to SARS-CoV-2 infection can provide a snapshot of the endogenous metabolic landscape of the host and its role in shaping the interaction with SARS-CoV-2. Disease severity and consequently the clinical outcomes may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. Hence, the host metabolome can help predict potential clinical risks and outcomes. Methods: In this prospective study, using a targeted metabolomics approach, we studied the metabolic signature in 154 COVID-19 patients (males=138, age range 48-69 yrs) and related it to disease severity and mortality. Blood plasma concentrations of metabolites were quantified through LC-MS using MxP Quant 500 kit, which has a coverage of 630 metabolites from 26 biochemical classes including distinct classes of lipids and small organic molecules. We then employed Kaplan-Meier survival analysis to investigate the correlation between various metabolic markers, disease severity and patient outcomes. Results: A comparison of survival outcomes between individuals with high levels of various metabolites (amino acids, tryptophan, kynurenine, serotonin, creatine, SDMA, ADMA, 1-MH and carnitine palmitoyltransferase 1 and 2 enzymes) and those with low levels revealed statistically significant differences in survival outcomes. We further used four key metabolic markers (tryptophan, kynurenine, asymmetric dimethylarginine, and 1-Methylhistidine) to develop a COVID-19 mortality risk model through the application of multiple machinelearning methods. Conclusions: Metabolomics analysis revealed distinct metabolic signatures among different severity groups, reflecting discernible alterations in amino acid levels and perturbations in tryptophan metabolism. Notably, critical patients exhibited higher levels of short chain acylcarnitines, concomitant with higher concentrations of SDMA, ADMA, and 1-MH in severe cases and non-survivors. Conversely, levels of 3-methylhistidine were lower in this context. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum asymmetric dimethylarginine (ADMA）, inhibin A (INH-A）and fetal growth restriction (FGR) in patients with early onset severe preeclampsia (SPE）. Methods: 110 patients with early onset SPE who were delivered in The First Affiliated Hospital of Hainan Medical University from January 2021 to January 2023 were selected as observation group, and 100 healthy pregnant women were selected as control group, patients with early onset SPE were divided into FGR group (46 cases) and no FGR group (64 cases) according to whether FGR was combined. The levels of serum ADMA and INH-A in observation group and control group were compared. The influencing factors of FGR in patients with early onset SPE were analyzed by multivariate Logistic regression analysis, the predictive effect of serum ADMA and INH-A levels on FGR in patients with early onset SPE were analyzed by receiver operating characteristic curve (ROC）. Results: Compared with control group, the levels of serum ADMA and INH-A in observation group were increased (P＜0.05）. Compared with no FGR group, the levels of ADMA, INH-A, systolic blood pressure, diastolic blood pressure, serum creatinine, 24 h urinary protein quantification, and umbilical artery blood flow end-systolic velocity/end-diastolic velocity ratio (S/D) were increased in FGR group, while the pre-pregnancy body mass index (BMI) was decreased (P＜0.05）. Multivariate Logistic regression analysis showed that, 24 h urinary protein quantification, arterial blood flow S/D, ADMA and INH-A were independent risk factors for FGR in patients with early onset SPE (P＜0.05）. ROC analysis showed that, the area under the curve of combined prediction of serum ADMA and INH-A levels in patients with early onset SPE complicated with FGR was greater than that of single prediction. Conclusion: The levels of serum ADMA and INH-A in patients with early onset SPE are abnormally increase, and are involve in the occurrence and development of FGR, in addition, the combination of serum ADMA and INH-A levels has a high predictive efficiency for FGR in patients with early onset SPE. [ABSTRACT FROM AUTHOR]

Prenatal exposure to maternal diabetes has been recognized as a significant cardiovascular risk factor, increasing the susceptibility to the emergence of conditions such as high blood pressure, atherosclerosis, and heart disease in later stages of life. However, it is unclear if offspring exposed to diabetes in utero have worse vascular outcomes on a high-salt (HS) diet. To test the hypothesis that in utero exposure to maternal diabetes predisposes to HS-induced vascular dysfunction, we treated adult male wild-type offspring (DM_Exp, 6 mo old) of diabetic Ins2+/C96Y mice (Akita mice) with HS (8% sodium chloride, 10 days) and analyzed endothelial function via wire myograph and cyclooxygenase (COX)-derived prostanoids pathway by ELISA, quantitative PCR, and immunochemistry. On a regular diet, DM_Exp mice did not manifest any vascular dysfunction, remodeling, or inflammation. However, HS increased aortic contractility to phenylephrine and induced endothelial dysfunction (analyzed by acetylcholine-induced endothelium-dependent relaxation), vascular hydrogen peroxide production, COX2 expression, and prostaglandin E2 (PGE2) overproduction. Interestingly, ex vivo antioxidant treatment (tempol) or COX1/2 (indomethacin) or COX2 (NS398) inhibitors improved or reverted the endothelial dysfunction in DM_Exp mice fed a HS diet. Finally, DM_Exp mice fed with HS exhibited greater circulating cytokines and chemokines accompanied by vascular inflammation. In summary, our findings indicate that prenatal exposure to maternal diabetes predisposes to HS-induced vascular dysfunction, primarily through the induction of oxidative stress and the generation of COX2-derived PGE2. This supports the concept that in utero exposure to maternal diabetes is a cardiovascular risk factor in adulthood. NEW & NOTEWORTHY: Using a unique mouse model of prenatal exposure to maternal type 1 diabetes, our study demonstrates the novel observation that prenatal exposure to maternal diabetes results in a predisposition to high-salt (HS) dietary-induced vascular dysfunction and inflammation in adulthood. Mechanistically, we demonstrated that in utero exposure to maternal diabetes and HS intake induces vascular oxidative stress, cyclooxygenase-derived prostaglandin E2, and inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Coronary slow flow phenomena (CSFP) are associated with endothelial and blood component abnormalities in coronary arteries. Asymmetric dimethylarginine (ADMA) can damage the endothelium of the heart or blood vessels in patients with non-valvular atrial fibrillation (NVAF), causing changes in levels of biological indicators. Our aim was to analyze the relationship between ADMA and CSFP in NVAF patients. Methods: We consecutively enrolled 134 patients diagnosed with NVAF and underwent coronary angiography, 50 control patients without a history of atrial fibrillation and with normal coronary angiographic flow were included at the same time. Based on the corrected TIMI frame count (CTFC), the NVAF patients were categorized into two groups, CTFC ≤27 frames and CTFC >27 frames. Plasma ADMA, P-selectin (p-sel), von Willebrand factor (vWF), D-dimer (D-Di), plasminogen activator inhibitor 1 (PAI-1), and nitric oxide (NO) were detected by ELISA in the different groups. Results: We found that plasma ADMA levels were significantly higher among NVAF patients in the CTFC >27 grade group compared with the control or CTFC ≤27 group. In addition, the levels of blood cells and endothelium-related biomarkers (NO, P-selectin, vWF, D-Di, and PAI-1) were significantly altered and correlated with ADMA levels. Multifactorial analysis showed that plasma ADMA (odd ratio [OR; 95% CI]: 1.65 [1.21–2.43], p < 0.001) and left atrial internal diameter (OR [95% CI]: 1.04 [1.02, 1.1], p < 0.001) could be used as independent risk factors for the development of CSFP in patients with NVAF. The ROC curves of ADMA can predict the development of CSFP in NVAF patients. The minimum diagnostic concentration for the development of CSFP in patients was 2.31 µmol/L. Conclusion: Our study demonstrated that CSFP in NVAF patients was associated with high levels of ADMA and left atrial internal diameter. Therefore, aggressive preoperative detection and evaluation of ADMA and left atrial internal diameter can help deal with the intraoperative presence of CSFP. [ABSTRACT FROM AUTHOR]

Nitraria roborowskii Kom. seeds have deep dormancy characteristics. Under natural conditions, the germination rate of the seeds is low, and the germination time is long. Therefore, exploring the reasons for seed dormancy is highly important. The results showed that the extracts of the methanol phase, ethyl acetate phase, petroleum ether phase and water phase of N. roborowskii seeds all had a significant inhibitory effect on the germination rate and germination index of Brassica rapa seeds, among which the extract of the methanol phase had the strongest inhibitory effect, and the inhibitory effect decreased in the following order from the strongest to the weakest: methanol phase > ethyl acetate phase > petroleum ether phase > water phase. The components of the methanol phase, ethyl acetate phase and petroleum ether phase ether extracts of N. roborowskii seeds were identified by gas chromatography–mass spectrometry (GC–MS). The experimental results showed that the organic phase extracts of N. roborowskii seeds contained a variety of inhibitory compounds, which included 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl-dibutyl phthalate; 4-((1E)-3-hydroxy-1-propenyl)-2-methoxyphenol; 13-docosenamide, (Z)-; 3-hydroxy-4-methoxybenzoic acid; vanillin; 2,4-di-tert-butylphenol; and cyclohexane, ethyl-. The seeds of N. roborowskii contain a variety of endogenous inhibitors, which are the main reason for its seed dormancy. [ABSTRACT FROM AUTHOR]

Background and Objectives: episodes of acute decompensation in chronic heart failure (ADHF), a common health problem for the growing elderly population, pose a significant socio-economic burden on the public health systems. Limited knowledge is available on both the endothelial function in and the cardio-metabolic health profile of old adults hospitalized due to ADHF. This study aimed to investigate the connection between asymmetric dimethylarginine (ADMA)—a potent inhibitor of nitric oxide—and key health biomarkers in this category of high-risk patients. Materials and Methods: this pilot study included 83 individuals with a known ADHF history who were admitted to the ICU due to acute cardiac decompensation. Selected cardiovascular, metabolic, haemogram, renal, and liver parameters were measured at admission to the ICU. Key renal function indicators (serum creatinine, sodium, and potassium) were determined again at discharge. These parameters were compared between patients stratified by median ADMA (114 ng/mL). Results: high ADMA patients showed a significantly higher incidence of ischemic cardiomyopathy and longer length of hospital stay compared to those with low ADMA subjects. These individuals exhibited significantly higher urea at admission and creatinine at discharge, indicating poorer renal function. Moreover, their lipid profile was less favorable, with significantly elevated levels of total cholesterol and HDL. However, no significant inter-group differences were observed for the other parameters measured. Conclusions: the present findings disclose multidimensional, adverse ADMA-related changes in the health risk profile of patients with chronic heart failure hospitalized due to recurrent decompensation episodes. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo evaluate the serum asymmetric dimethylarginine (ADMA) level as a biomarker for uveitis in Behçet’s Disease (BD).In this cross-sectional study, two groups of BD patients were examined: 33 with uveitis and 27 without uveitis. All patients were clinically evaluated, with disease activity measured by Behçet’s Disease Current Activity Form (BDCAF) score. They also underwent thorough ophthalmic evaluation, and routine laboratory investigations, including serum ADMA.Patients with BD who experienced active or inactive uveitis had higher levels of serum ADMA compared to those without uveitis. Anterior (ρ = 0.34, p < 0.01), posterior (ρ = 0.3, p < 0.05), and pan uveitis (ρ = 0.35, p < 0.01) were significantly correlated with serum ADMA levels. However, there was no significant correlation between ADMA and other BD manifestations. ROC curve analysis showed that increased serum ADMA levels in BD patients predicted uveitis with a sensitivity of 61.8%, specificity of 96.2%, and AUC of 0.78(95% CI: 0.66–0.9, p < 0.001).Serum ADMA level can serve as a novel biomarker of uveitis in BD and its severity with good diagnostic accuracy, regardless of its site or activity. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 1 (PRMT1) is a major type I arginine methyltransferase that catalyzes the formation of monomethyl and asymmetric dimethylarginine in protein substrates. It was first identified to asymmetrically methylate histone H4 at the third arginine residue forming the H4R3me2a active histone mark. However, several protein substrates are now identified as being methylated by PRMT1. As a result of its association with diverse classes of substrates, PRMT1 regulates several biological processes like chromatin dynamics, transcription, RNA processing, and signal transduction. The review provides an overview of PRMT1 structure, biochemical features, specificity, regulation, and role in cellular functions. We discuss the genomic distribution of PRMT1 and its association with tRNA genes. Further, we explore the different substrates of PRMT1 involved in splicing. In the end, we discuss the proteins that interact with PRMT1 and their downstream effects in diseased states. [ABSTRACT FROM AUTHOR]

Aim: Nymphaea plants were traditionally used to treat diseases associated with endothelial dysfunction. The present study investigated the effects of an ethanolic extract of Nymphaea pubescens Willd. (commonly named water lily, WL) and its main compound 1 (quercetin 3-methyl ether 3'-O-β-xylopyranoside) on vascular function in rats. Materials and methods: The vasorelaxant effects of the WL extract and its main compound 1 and their underlying mechanisms of action were evaluated on isolated mesenteric arteries from Wistar rats. Blood pressure and heart ratewere measured in anesthetized rats after infusion (i.v) of vehicle, WL extract, and compound 1 (at 0.01, 0.025, 0.05, 0.1, 0.5, and 1mg/kg). Nifedipine was used as a positive control. Results: Both WL extract and compound 1 induced vasorelaxant effects (with EC50 of 0.08 ± 0.01mg/mL and 42.8 ± 6.3 µM, respectively) that were reduced by endothelium removal. A significant decrease in these relaxations was observed with L-NAME but not with apamin--charybdotoxin or indomethacin. In the endotheliumdenuded condition, WL extract-induced relaxation was enhanced by 4-aminopyridine and glibenclamide, while iberiotoxin and ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one) had no effect. In contrast, compound 1-induced relaxation was not changed by any of these inhibitors. Both WL extract and compound 1 enhanced sodium nitroprusside-induced relaxation and inhibited receptor-operated Ca2+ channels.Only the WL extract was able to reduce PE-induced contraction (p < 0.001). As compared to the vehicle, the infusion of WL extract and compound 1 lowered systolic and diastolic blood pressure. Interestingly, the hypotensive effect of the compound was similar to that of nifedipine. The rebound tachycardia found at the highest dose of nifedipine was not observed with the WL extract or compound 1 (p < 0.05). Conclusion and discussion: Our study demonstrated a vasorelaxant effect of the WLextract and itsmain compound quercetin 3-methyl ether 3'-O-β-xylopyranoside, relying on the potentiation of the NO-cGMP pathway and calcium inhibitory effects. These vasorelaxant effects were associated with a potent hypotensive effect, providing pharmacological evidence for the traditional use of this plant. [ABSTRACT FROM AUTHOR]

Performing cardiac surgery under cardiopulmonary bypass (CPB) and circulatory arrest (CA) provokes the development of complications caused by tissue metabolism, microcirculatory disorders, and endogenous nitric oxide (NO) deficiency. This study aimed to investigate the potential mechanisms for systemic organoprotective effects of exogenous NO during CPB and CA based on the assessment of dynamic changes in glycocalyx degradation markers, deformation properties of erythrocytes, and tissue metabolism in the experiment. A single-center prospective randomized controlled study was conducted on sheep, n = 24, comprising four groups of six in each. In two groups, NO was delivered at a dose of 80 ppm during CPB ("CPB + NO" group) or CPB and CA ("CPB + CA + NO"). In the "CPB" and "CPB + CA" groups, NO supply was not carried out. NO therapy prevented the deterioration of erythrocyte deformability. It was associated with improved tissue metabolism, lower lactate levels, and higher ATP levels in myocardial and lung tissues. The degree of glycocalyx degradation and endothelial dysfunction, assessed by the concentration of heparan sulfate proteoglycan and asymmetric dimethylarginine, did not change when exogenous NO was supplied. Intraoperative delivery of NO provides systemic organoprotection, which results in reducing the damaging effects of CPB on erythrocyte deformability and maintaining normal functioning of tissue metabolism. [ABSTRACT FROM AUTHOR]

Mastitis is a significant infectious disease in dairy cows, resulting in milk yield loss and culling. Early detection of mastitis-prone cows is crucial for implementing effective preventive measures before disease onset. Current diagnosis of subclinical mastitis (SCM) relies on somatic cell count assessment post-calving, lacking predictive capabilities. This study aimed to identify metabolic changes in pre-SCM cows through targeted metabolomic analysis of urine samples collected 8 wks and 4 wks before calving, using mass spectrometry. A nested case-control design was employed, involving a total of 145 multiparous dairy cows, with disease occurrence monitored pre- and postpartum. Among them, 15 disease-free cows served as healthy controls (CON), while 10 cows exclusively had SCM, excluding those with additional diseases. Urinary metabolite profiling revealed multiple alterations in acylcarnitines, amino acids, and organic acids in pre-SCM cows. Metabotyping identified 27 metabolites that distinguished pre-SCM cows from healthy CON cows at both 8 and 4 wks before parturition. However, only four metabolites per week showed significant alterations (p < 0.005). Notably, a panel of four serum metabolites (asymmetric dimethylarginine, proline, leucine, and homovanillate) at 8 wks prepartum, and another panel (asymmetric dimethylarginine, methylmalonate, citrate, and spermidine) at 4 wks prepartum, demonstrated predictive ability as urinary biomarkers for SCM risk (AUC = 0.88; p = 0.02 and AUC = 0.88; p = 0.03, respectively). In conclusion, our findings indicate that metabolite testing can identify cows at risk of SCM as early as 8 and 4 wks before parturition. Validation of the two identified metabolite panels is warranted to implement these predictive biomarkers, facilitate early intervention strategies, and improve dairy cow management to mitigate the impact of SCM. Further research is needed to confirm the efficacy and applicability of these biomarkers in practical farm settings. [ABSTRACT FROM AUTHOR]

Bacterial outer membrane vesicles (OMVs) contain a variety of chemical compounds and play significant roles in maintaining symbiotic relationships in a changing ocean, but little is known about their function, particularly in sponge larval development. During the growth of sponge Tedania sp., OMVs from Bacteroidetes species significantly promoted larval settlement, and Tenacibaculum mesophilum SP-7-OMVs were selected as a representative strain for further investigation. According to OMVs metabolomics, larval settlement might be connected to organic acids and derivatives. The multiomics analysis of the T. mesophilum genome, SP-7-OMVs metabolome, and larval transcriptome revealed 47 shared KEGG pathways. Among the number of candidate metabolites, arginine was chosen for its greater ability to increase the settlement rate and its role as the principal substrate for nitric oxide (NO) synthesis of sponge larvae. In summary, these results demonstrated that sponge-associated bacteria might utilize OMVs and their cargo to support host development and make up for host metabolic pathway deficiencies. This study enhances our fundamental knowledge of OMVs in interactions between metazoan hosts andmicroorganisms that are crucial in the coevolution of marine ecosystems and the complex marine environment. [ABSTRACT FROM AUTHOR]

Recently, arginine has been proven to play an important role in ADPKD physiopathology. Arginine auxotrophy in ADPKD induces cell hyperproliferation, blocking the normal differentiation of renal tube cells and causing cyst formation. We explored the L-arginine (Arg)–nitric oxide (NO) molecular pathway in ADPKD, a multisystemic arginine auxotrophe disease. We developed a prospective case–control study that included a group of 62 ADPKD subjects with an estimated filtration rate over 60 mL/min/1.73 mp, 26 subjects with chronic kidney disease with an eGFR > 60 mL/min/1.73 mp, and a group of 37 healthy subjects. The laboratory determinations were the serum level of arginine, the enzymatic activity of arginase 2 and inducible nitric oxide synthase, the serum levels of the stable metabolites of nitric oxide (nitrate, direct nitrite, and total nitrite), and the endogenous inhibitors of nitric oxide synthesis (asymmetric dimethylarginine and symmetric dimethylarginine). In the ADPKD group, the levels of the arginine and nitric oxide metabolites were low, while the levels of the metabolization enzymes were higher compared to the control group. Statistical analysis of the correlations showed a positive association between the serum levels of Arg and the eGFR and a negative association between Arg and albuminuria. ADPKD is a metabolic kidney disease that is auxotrophic for arginine. Exploring arginine reprogramming and L-Arg–NO pathways could be an important element in the understanding of the pathogenesis and progression of ADPKD. [ABSTRACT FROM AUTHOR]

Background: Serum symmetric dimethylarginine (SDMA) is used to screen for renal dysfunction in dogs. The gold standard technique for measuring SDMA, liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) is not widely available. Age‐specific reference intervals for SDMA in older dogs are lacking. Objectives: Prospective study in older dogs to validate a commercially available LC‐MS/MS method for SDMA, compare SDMA concentrations with concentrations measured using ELISA and obtain a reference interval (RI) for older dogs using both methods. Animals: Client‐owned older dogs undergoing health screening. Methods: The LC‐MS/MS method was analytically validated (limit of detection, precision, and linearity). Serum was sent cooled overnight for ELISA or was frozen at −80°C until batch analysis using LC‐MS/MS. Results of LC‐MS/MS and ELISA were compared and RIs for older dogs were calculated according to international guidelines. Results: The LC‐MS/MS method showed good linearity (r2 =.99) and precision (coefficient of variation <10%), with a laboratory RI between 8.0 and 14.0 μg/dL. Paired measurements were available from 118 different dogs. Median SDMA concentration were 9.4 (range, 5.0‐21.2) using LC‐MS/MS and 12.0 (range, 5.0‐22.0) μg/dL using ELISA. Both methods significantly differed with a mean difference of 2.2 μg/dL. The RI for older dogs for LC‐MS/MS was 4.4‐15.0 μg/dL, and for ELISA was 6.4‐17.4 μg/dL. Conclusions and Clinical Importance: The ELISA provided significantly higher SDMA concentrations compared to the validated LC‐MS/MS method, indicating the need for device‐ or assay‐specific RI. The obtained age‐specific RI for SDMA is considerably higher in older dogs compared to the general laboratory RI. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR. [ABSTRACT FROM AUTHOR]

PYCARD (PYD and CARD domain containing), a pivotal adaptor protein in inflammasome assembly and activation, contributes to innate immunity, and plays an essential role in the pathogenesis of atherosclerosis and restenosis. However, its roles in microRNA biogenesis remain unknown. Therefore, this study aimed to investigate the roles of PYCARD in miRNA biogenesis and neointima formation using pycard knockout (pycard−/−) mice. Deficiency of Pycard reduced circulating miRNA profile and inhibited Mir17 seed family maturation. The systemic pycard knockout also selectively reduced the expression of AGO2 (argonaute RISC catalytic subunit 2), an important enzyme in regulating miRNA biogenesis, by promoting chaperone-mediated autophagy (CMA)-mediated degradation of AGO2, specifically in adipose tissue. Mechanistically, pycard knockout increased PRMT8 (protein arginine N-methyltransferase 8) expression in adipose tissue, which enhanced AGO2 methylation, and subsequently promoted its binding to HSPA8 (heat shock protein family A (Hsp70) member 8) that targeted AGO2 for lysosome degradation through chaperone-mediated autophagy. Finally, the reduction of AGO2 and Mir17 family expression prevented vascular injury-induced neointima formation in Pycard-deficient conditions. Overexpression of AGO2 or administration of mimic of Mir106b (a major member of the Mir17 family) prevented Pycard deficiency-mediated inhibition of neointima formation in response to vascular injury. These data demonstrate that PYCARD inhibits CMA-mediated degradation of AGO2, which promotes microRNA maturation, thereby playing a critical role in regulating neointima formation in response to vascular injury independently of inflammasome activity and suggest that modulating PYCARD expression and function may represent a powerful therapeutic strategy for neointima formation. Abbreviations: 6-AN: 6-aminonicotinamide; ACTB: actin, beta; aDMA: asymmetric dimethylarginine; AGO2: argonaute RISC catalytic subunit 2; CAL: carotid artery ligation; CALCOCO2: calcium binding and coiled-coil domain 2; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSD: cathepsin D; DGCR8: DGCR8 microprocessor complex subunit; DOCK2: dedicator of cyto-kinesis 2; EpiAdi: epididymal adipose tissue; HSPA8: heat shock protein family A (Hsp70) member 8; IHC: immunohistochemical; ISR: in-stent restenosis; KO: knockout; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; miRNA: microRNA; NLRP3: NLR family pyrin domain containing 3; N/L: ammonium chloride combined with leupeptin; PRMT: protein arginine methyltransferase; PVAT: peri-vascular adipose tissues; PYCARD: PYD and CARD domain containing; sDMA: symmetric dimethylarginine; ULK1: unc-51 like kinase 1; VSMCs: vascular smooth muscle cells; WT: wild-type. [ABSTRACT FROM AUTHOR]

Background: ω-NG,NG-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN). Objective: To investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine N-methyltransferase 1 gene (PRMT1) influence ADMA dynamics and DN incidence and severity. Methods: This study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of PRMT1-related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. PRMT1 mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated. Results: The composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 (p = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12–7.62, p = 0.028), along with higher PRMT1 mRNA, serum ADMA levels, and baPWV than the GG subgroup (p

Cerebral asymmetry is critical for typical brain function and development; at the same time, altered brain lateralization seems to be associated with neuropsychiatric disorders. Zebrafish are increasingly emerging as model species to study brain lateralization, using asymmetric development of the habenula, a phylogenetically old brain structure associated with social and emotional processing, to investigate the relationship between brain asymmetry and social behavior. We exposed 5-h post-fertilization zebrafish embryos to valproic acid (VPA), a compound used to model the core signs of ASD in many vertebrate species, and assessed social interaction, visual lateralization and gene expression in the thalamus and the telencephalon. VPA-exposed zebrafish exhibit social deficits and a deconstruction of social visual laterality to the mirror. We also observe changes in the asymmetric expression of the epithalamic marker leftover and in the size of the dorsolateral part of the habenula in adult zebrafish. Our data indicate that VPA exposure neutralizes the animals' visual field bias, with a complete loss of the left-eye use bias in front of their own mirror image, and alters brain asymmetric gene expression and morphology, opening new perspectives to investigate brain lateralization and its link to atypical social cognitive development. [ABSTRACT FROM AUTHOR]

The identification of circulating biomarkers of endothelial dysfunction (ED), a precursor to atherosclerosis, in rheumatoid arthritis (RA) would facilitate early risk stratification and prevention strategies. Ischemia-modified albumin (IMA) has emerged as a potential biomarker of oxidative stress, ischemia, and ED. However, studies examining the relationship between IMA and ED in RA patients are lacking. We measured serum IMA concentrations by using an albumin cobalt binding test and peripheral vasodilatory capacity by EndoPAT in 113 RA patients without previous cardiovascular events enrolled in the EDRA study (ClinicalTrials.gov: NCT02341066). The mean peripheral vasodilatory capacity, expressed by the log of reactive hyperemia index (logRHI), was 0.82, corresponding to 27% RA patients having ED. The mean plasma concentrations of IMA were 0.478 absorbance units. We observed a significant and inverse association between peripheral vasodilatory capacity and serum IMA concentrations (rho = − 0.22, p = 0.02). In univariate logistic regression, ED was significantly associated with serum IMA concentrations [OR 1173 (95% CI 1.3568 to 101,364), p = 0.040) and higher disease activity. In multivariate logistic regression, the independent association between ED and IMA remained significant after correction for disease activity and other RA-confounders [OR 2252 (95% CI 1.0596 to 4,787,505), p = 0.048 in Model 1; OR 7221 (95% CI 4.1539 to 12,552,859), p = 0.02 in Model 2]. Conclusions: This study suggests that IMA is a promising biomarker of ED in RA. Further research is needed to confirm our findings and determine the clinical utility of IMA in detecting and managing early atherosclerosis in RA patients. [ABSTRACT FROM AUTHOR]

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation. [ABSTRACT FROM AUTHOR]

Background: Remnant cholesterol (RC) represents a low-cost and readily measured lipid index that contributes significantly to residual cardiovascular disease risk. The triglyceride-glucose (TyG) index exhibits a significant correlation with cardiovascular disease occurrence. However, RC and the TyG index have rarely been examined for their potentials in predicting coronary artery disease (CAD). Accordingly, the study was designed to validate the correlations of these two biomarkers with CAD and to compare the forecasted values of these two biomarkers for newly diagnosed CAD. Methods: Totally 570 subjects firstly administered coronary angiography were enrolled, including 431 newly diagnosed CAD cases and 139 individuals without CAD. The individuals were classified into two groups according to CAD diagnosis. RC was derived as total cholesterol content (mmol/L) – (high density lipoprotein cholesterol content + low density lipoprotein cholesterol content; both in mmol/L). The TyG index was determined as ln (fasting triglyceride level [mg/dL] × fasting plasma glucose level [mg/dL])/2. Results: Baseline feature analysis revealed significant differences in RC and the TyG index between the CAD and non-CAD groups (both P < 0.001). RC and the TyG index were independent risk factors for CAD in accordance with logistic regression analysis (both P < 0.05). Moreover, spearman correlation analysis elucidated CAD had a more remarkable correlation with the TyG index compared with RC (both P < 0.001). Furthermore, according to receiver operating characteristic curve analysis, the TyG index was better than RC in predicting CAD. Conclusions: The TyG index and RC have significant associations with CAD. Compared with RC, the TyG index possesses a closer correlation with CAD and a higher predictive value for CAD. [ABSTRACT FROM AUTHOR]

The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-aminolevulinic acid synthase (ALAS) to promote pyridoxal phosphate (PLP) binding. CLPX may also influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted a reduction in arginine/histidine levels. In Mus musculus cerebellum, reductions in arginine/histidine and citrulline occurred with a concomitant accumulation of the heme precursor protoporphyrin IX. This suggests that the increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA and C1 glycine but also specific C5 delta amino acids. As enzymes responsible for these effects, the elevated abundance of CLPX and ALAS is paralleled by increased OAT (PLP-dependent, ornithine delta-aminotransferase) levels. Possibly as a consequence of altered C1 metabolism, the proteome profiles of P. anserina CLPP-null cells showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. The reduced histidine levels may explain the previously observed metal interaction problems. As the main nitrogen-storing metabolite, a deficiency in arginine would affect the urea cycle and polyamine synthesis. Supplementation of arginine and histidine might rescue the growth deficits of CLPP-mutant patients. [ABSTRACT FROM AUTHOR]

The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin–angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline's ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats. [ABSTRACT FROM AUTHOR]